title: Differential cystine and dibasic amino acid handling after loss of function of the amino acid transporter b0,+AT (Slc7a9) in mice.
abstract: Cystinuria is an autosomal recessive disease caused by mutations in SLC3A1 (rBAT) and SLC7A9 (b(0,+)AT). Gene targeting of the catalytic subunit (Slc7a9) in mice leads to excessive excretion of cystine, lysine, arginine, and ornithine. Here, we studied this non-type I cystinuria mouse model using gene expression analysis, Western blotting, clearance, and brush-border membrane vesicle (BBMV) uptake experiments to further characterize the renal and intestinal consequences of losing Slc7a9 function. The electrogenic and BBMV flux studies in the intestine suggested that arginine and ornithine are transported via other routes apart from system b(0,+). No remarkable gene expression changes were observed in other amino acid transporters and the peptide transporters in the intestine and kidney. Furthermore, the glomerular filtration rate (GFR) was reduced by 30% in knockout animals compared with wild-type animals. The fractional excretion of arginine was increased as expected (∼100%), but fractional excretions of lysine (∼35%), ornithine (∼16%), and cystine (∼11%) were less affected. Loss of function of b(0,+)AT reduced transport of cystine and arginine in renal BBMVs and completely abolished the exchanger activity of dibasic amino acids with neutral amino acids. In conclusion, loss of Slc7a9 function decreases the GFR and increases the excretion of several amino acids to a lesser extent than expected with no clear regulation at the mRNA and protein level of alternative transporters and no increased renal epithelial uptake. These observations indicate that transporters located in distal segments of the kidney and/or metabolic pathways may partially compensate for Slc7a9 loss of function.
authors.affiliation: Institute of Physiology-Zurich Center for Integrative Human Physiology (ZIHP University of Zurich, Winterthurerstrasse 190, CH-8075 Zurich, Switzerland. wagnerca@access.uzh.ch.
authors.forename: Andrea
authors.initials: A
authors.lastname: Di Giacopo
authors.forename: Isabel
authors.initials: I
authors.lastname: Rubio-Aliaga
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cantone
authors.forename: Ferruh
authors.initials: F
authors.lastname: Artunc
authors.forename: Rexhep
authors.initials: R
authors.lastname: Rexhepaj
authors.forename: Isabelle
authors.initials: I
authors.lastname: Frey-Wagner
authors.forename: Mariona
authors.initials: M
authors.lastname: Font-Llitjós
authors.forename: Nicole
authors.initials: N
authors.lastname: Gehring
authors.forename: Gerti
authors.initials: G
authors.lastname: Stange
authors.forename: Isabel
authors.initials: I
authors.lastname: Jaenecke
authors.forename: Nilufar
authors.initials: N
authors.lastname: Mohebbi
authors.forename: Ellen I
authors.initials: EI
authors.lastname: Closs
authors.forename: Manuel
authors.initials: M
authors.lastname: Palacín
authors.forename: Virginia
authors.initials: V
authors.lastname: Nunes
authors.forename: Hannelore
authors.initials: H
authors.lastname: Daniel
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.forename: Giovambattista
authors.initials: G
authors.lastname: Capasso
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Wagner
mesh_terms: D026923:Amino Acid Transport Systems, Basic / Q000172:deficiency* / Q000235:genetics; D000599:Amino Acids, Diamino / Q000378:metabolism*; D000818:Animals; D003553:Cystine / Q000378:metabolism*; D003555:Cystinuria / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D005919:Glomerular Filtration Rate / Q000502:physiology; D007668:Kidney / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D026923:Amino Acid Transport Systems, Basic; D000599:Amino Acids, Diamino; C499488:Slc7a9 protein, mouse; D003553:Cystine
keywords: GFR; SLC7A9; cystine; cystinuria; peptide transporter